We are seeking funds in response to NOT-OD-09-058 "NIH American Recovery Act Funds for Competitive Revision Applications" to allow us to expand our specific aim 3 of our approved parent award. All three specific aims of our parent award are based on molecular, cellular, and biochemical studies to elucidate three novel steps in the regulation of inflammasome assembly and activity in macrophages. With this revision, we are proposing to include a novel sub aim to our approved aim 3 to translate our in vitro studies into in vivo animal models. Based on our progress with specific aim 3, we propose to generate a macrophage-specific conditional knock out mouse to study inflammasome activity in knock-out macrophages in vitro, and in inflammasome- dependent disease models in vivo. We request funds to cover the generation of this mouse model and that of technical support for the animal work. This revision will increase the scope of our approved parent award and enable our laboratory to establish mouse disease models. Funding of this revision will support the objectives of the American Recovery and Reinvestment Act of 2009 to create "new research employment opportunities" and "to bolster small US businesses and the US economy". PUBLIC HEALTH RELEVANCE: Excessive production of IL-12 and IL-18 are directly responsible for the symptoms of an increasing number of inflammatory diseases with destructive pathogenesis, including some of the most common diseases of industrialized nations, such as arthritis, asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis, periodontitis, type 2 Diabetes, lung fibrosis, multiple sclerosis, Alzheimer's disease, stroke, or cancer. Currently there are no effective treatments available, causing patient's life-long symptoms and a huge economical and financial impact on our social and medical systems. Therefore, this study on novel mechanisms that regulate production of IL-12 and IL-18 is expected to positively affect human health by providing the basis for the development of novel and improved treatment options for preventing uncontrolled release of IL-12 and IL-18 in patients suffering from inflammatory diseases.